Emerging virus infections are a substantial global public health threat, in part due to the difficulties in responding to contain or treat previously unknown or uncharacterized pathogens. These emerging viruses can cause a diverse variety of disease phenotypes, ranging from mild subclinical infections to severe, highly lethal clinical manifestations such as hemorrhagic fever, encephalitis, and acute respiratory distress syndrome. The broad range of illnesses underscores the need for a framework enabling both rapid diagnosis and prognostic considerations to inform subsequent clinical and epidemiological strategies. Systems biology approaches complement classical methods for investigating emerging pathogens that depend on cultivation of the etiologic agent. By developing diagnostic and prognostic measures based on host responses to known and emerging pathogens, we can avoid issues associated with rapidly developing a robust experimental model for a new virus and substantially hasten the development of informed therapeutic strategies. Through close collaboration with other investigators in the center we plan to develop a reliable, comprehensive, and versatile platform for using host response signatures as diagnostic and prognostic tools. We plan to first use established disease models that are themselves based on emergent viruses, including both cell culture and animal models. Using signatures developed by computational integration of multiple datasets from models, we will apply these methods to newly emerging viruses. Finally, we will use our findings to mine existing drug databases to identify therapeutics that can be repurposed quickly and efficiently for treating these emerging diseases. In each of our Specific Aims, we will use high-throughput transcriptional profiling and novel non-linear geometric as well as machine learning computational methods to define genome-wide gene-activity biomeasures diagnostic of severe disease, prognostic indicators of disease outcome, and identify new potential host therapeutic targets for inducing antiviral effects and/or attenuating disease severity. In addition, we will garner new knowledge related to common and distinct mechanisms of pathogenesis and the host responses that determine eventual disease outcome.